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Teriflunomide
Aubagio
DHODH inhibitor (active metabolite of leflunomide; FDA-approved)
Evidence Score
22
Teriflunomide is the pharmacologically active metabolite of leflunomide (Arava, FDA-approved for rheumatoid arthritis and psoriatic arthritis since 1998) and is itself FDA-approved for relapsing forms of multiple sclerosis (Aubagio, approved 2012). Both drugs inhibit DHODH (dihydroorotate dehydrogenase), the mitochondrial enzyme at step 4 of de novo pyrimidine synthesis. The mechanistic rationale for SDH-deficient tumors is identical to brequinar: SDH loss suppresses upstream pyrimidine synthesis at the ATCase step (succinate-mediated; Hart et al., Nat Metab 2026, PMID 42082831), and teriflunomide's DHODH inhibition compounds this partial block, selectively starving SDH-deficient cells of pyrimidines while normal cells tolerate the additional burden via intact upstream pathway flux. The principal advantage of teriflunomide over brequinar is clinical accessibility: it is an FDA-approved, orally available medication with a well-characterized long-term safety profile from MS and RA use, enabling rapid off-label evaluation. Teriflunomide also showed anti-tumor activity in a Phase 2 study in glioblastoma (NCT02799498), demonstrating broad oncologic penetration and providing proof-of-concept for the DHODH-inhibition cancer strategy outside its approved indications. Teriflunomide has a half-life of ~18 days and undergoes enterohepatic circulation, which complicates dose titration but enables once-daily oral dosing. Key limitations: (1) no SDH-deficient-specific data for teriflunomide; (2) teriflunomide's anti-proliferative efficacy in cancer may be confounded by its immunosuppressive activity (T-lymphocyte pyrimidine dependency), making tumor versus immune effects difficult to separate in vivo; (3) the glioblastoma Phase 2 was exploratory; (4) direct comparison with brequinar's potency against DHODH shows teriflunomide has lower enzyme affinity (IC50 ~600 nM vs. brequinar ~3 nM), suggesting brequinar may be the preferred candidate for SDH-deficient cancer testing once SDH-specific preclinical experiments validate the direction.
SDH loss creates a dual block in de novo pyrimidine synthesis: (1) TCA cycle truncation depletes the aspartate pool (aspartate is a required nitrogen and carbon donor for the pyrimidine ring), and (2) accumulated succinate directly and competitively inhibits aspartate transcarbamylase (ATCase/CAD), the enzyme that commits aspartate to carbamoyl aspartate — the second step of pyrimidine synthesis (Hart et al., Nat Metab 2026, PMID 42082831). This dual impairment leaves SDH-deficient cells near a pyrimidine synthesis floor, with far less buffer to absorb additional de novo pathway blockade compared with normal cells. DHODH inhibitors (blocking dihydroorotate → orotate, step 4 of the same de novo pathway) selectively tip SDH-deficient cells into pyrimidine starvation while normal cells — with intact ATCase and adequate aspartate — sustain sufficient UMP production.
Upstream event:
SDH loss → succinate accumulation → (1) OAA/aspartate pool depletion via TCA truncation + (2) direct succinate-mediated inhibition of ATCase (CAD) → de novo pyrimidine synthesis suppression
Downstream effects:
DHODH
Dihydroorotate dehydrogenase (mitochondrial)
Mitochondrial inner-membrane flavoenzyme catalyzing the fourth step of de novo pyrimidine synthesis: dihydroorotate → orotate (coupled to the reduction of ubiquinone). DHODH is the only step in pyrimidine biosynthesis that is mitochondrially located and strictly dependent on a functional electron transport chain to re-oxidize FMNH2. In SDH-deficient cells, de novo pyrimidine synthesis is already suppressed by the succinate-mediated block at ATCase (step 2), leaving residual pathway flux dependent on DHODH at step 4. Inhibiting DHODH compounds this pre-existing block, selectively depleting SDH-deficient cells of UMP and downstream pyrimidines. Normal cells, with intact ATCase and adequate aspartate supply, have substantially more reserve to tolerate DHODH inhibition. Targeted by brequinar (DUP-785) and by leflunomide/teriflunomide (FDA-approved for rheumatoid arthritis / relapsing MS). Primary anchor reference: Hart et al., Nat Metab 2026, PMID 42082831.
UniProt: Q02127
Tumor Type Applicability
Approved Indications
- Relapsing forms of multiple sclerosis (including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS)
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
For research exploration only — not medical advice. Consult your doctor before acting on any information.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.